Charles Steward, PhD, Clinical Domain Lead for Epilepsy, Congenica
Epilepsy has a profound effect on patients, families and carers. Furthermore, the burden to healthcare providers is enormous.
As a result, large scale sequencing collaborations such as Epi25, the Deciphering Developmental Disorders study and the UK 100,000 Genomes Project are using chromosomal microarrays, whole exome sequencing (WES) and whole genome sequencing (WGS) to investigate the genetic causes of many rare disorders that include epilepsy.
These projects will expedite patient molecular diagnoses, as well as opportunities for the pharmaceutical industry to provide novel therapies.
Here, we shine a light on the benefits that a genetic diagnosis can bring to people affected by epilepsy and the promise that genomic medicine holds.
Background to epilepsy
Epilepsy is characterized by two or more unprovoked seizures, due to abnormal, synchronized neuronal firing in the brain.
More than 60 million people worldwide have epilepsy, including three million people in the USA and 500,000 people in the UK and with nearly 80% of people with epilepsy living in low- and middle-income countries.
One in 20 people will have a one-off seizure at some point in their life, although this does not necessarily mean they have epilepsy and one in 50 people will have epilepsy at some time in their life.
Although epilepsy is most commonly diagnosed in children and people over 65, epilepsy can occur at any time of life and to anyone of any race, sex or age, making it highly unpredictable.
There are more than 60 different types of seizure and not all seizures involve convulsions, unconsciousness and shaking. More broadly speaking, the International League Against Epilepsy (ILAE) divides seizures into groups; depending on where they start in the brain, if the patient’s awareness is affected and whether or not
the seizures involve any other symptoms. If a specific part of the brain is involved, seizures are described as focal; if both sides of the brain are affected, these seizures are described as generalized.
There are more than 30 types of epilepsy syndromes, which include some of the most severe and debilitating forms seen in very young children in the first months of life. These include Ohtahara syndrome, Dravet syndrome and West syndrome.
Understanding the causes
The causes of epilepsy are complex; they may result from damage caused to the brain through injury, such as trauma experienced through an accident or a problematic birth, brain tumors or viral and bacterial infections like meningitis, as well as many genetic factors.
Causes can also include structural changes in the brain, due to genetic conditions, such as tuberous sclerosis or neurofibromatosis, which cause growths affecting the brain. Therefore, making a diagnosis for a patient can be extremely challenging.
There are also many important comorbidities associated with epilepsy that generally fall into two broad categories - those that are presumed to cause epilepsy, such as cerebral palsy and neurologic congenital malformations and those that are a result of epilepsy, such as autism, intellectual disability and developmental delay.
Epilepsy is associated with many different clinical phenotypes and genotypes. The mode of inheritance can be recessive, dominant, de novo (a new variant not present in parents) or X-linked. It is further complicated by complex inheritance patterns and the effect that the environment may play.
The impact on patients
Epilepsy can have a profound effect on a patient’s outcome in life. Epilepsy is particularly severe in infants, where uncontrolled seizures in the developing brain can cause developmental regression and, in some cases, early death. In the UK, there are around 1,000 deaths per year as a result of epilepsy of which 42% are potentially preventable including status epilepticus, accidents and unintentional injuries.
Furthermore, anyone with epilepsy has a very small but raised risk of sudden unexpected death in epilepsy (SUDEP). SUDEP is the most common cause of epilepsy-related deaths and individuals with epilepsy have 27-fold higher rates of sudden death than individuals without epilepsy.
Treatments for epilepsy
Anti-epileptic drugs (AEDs)
Epilepsy is usually treated with medications called anti-epileptic drugs (AEDs). AEDs aim to stop seizures from happening, but they do not cure epilepsy. With prescription of the correct AEDs, up to 70% of people with epilepsy will have their seizures controlled.
The main groups of AEDs include sodium channel blockers, calcium current inhibitors, GABA enhancers, glutamate blockers, carbonic anhydrase inhibitors and hormones.
According to the Epilepsy Society, there are at least 27 AEDs used to treat seizures and different AEDs work for different seizures. The response, in terms both of seizure control and adverse drug reactions to AEDs, varies greatly across individuals.
However, AEDs are not without complications, for example, anticonvulsants, such as valproate, can have serious side effects on the developing embryo if taken during pregnancy.
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that is an effective treatment for some hard-to-treat epilepsies, while cannabidiol is another promising treatment, although its effectiveness is still under debate.
Brain surgery can be another option, as is deep brain stimulation, while vagus nerve stimulation is the best known of the neuromodulation therapies where a device sends electrical impulses to the brain that help to reduce severity of seizures.
How is genomic medicine supporting epilepsy patients?
Genome sequencing has revealed that a large proportion of previously ‘unknown’ epilepsies have
This includes epilepsies caused by single genes, epilepsies with complex inheritance and modifiers and susceptibility alleles, although the exact proportion of these epilepsies remains uncertain.
The genes associated with epilepsy grow ever larger as new discoveries are made about gene function. Experts have now recognized that variants in a single gene can bring about several different phenotypes, making it difficult for a clinician to pin-point a single gene for any given phenotype.
While most patients with epilepsy are treated with no knowledge of an underlying genotype, a detailed understanding of a patient’s genome offers the promise of more targeted treatment based upon the patient’s genomic makeup.
Therefore, a genetic diagnosis is important on many levels. For more effective and personalized treatment, family planning, more accurate knowledge of how the disorder might develop, and facilitating access to healthcare and patient support services.
Achieving a faster epilepsy diagnosis
The importance of rapid genome analysis, particularly for critically ill children, cannot be overstated. Early intervention can potentially provide actionable outcomes that could prevent irreversible malfunctioning of the brain.
Crucially, it is thought that at least 40% of neurodevelopmental disorders in infants are a result of a de novo variant. This is of particular importance considering there are only around 70 de novo variants present in a patient’sgenome compared to the mother and father.
In general, it is possible to identify a genetic cause in about 40% of Developmental and Epileptic Encephalopathy cases. Interestingly, in a publication by Helbig et al (2016), where 40% of the cases had an identified genetic aetiology, 75% of these were a result of a de novo pathogenic variant. The younger the age of onset, the higher the yield meaning that a genomic investigation has a reasonable chance of yielding a positive genetic result.
In a significant proportion of children, these results are leading directly to tailored therapy and a change in patient management, illustrating the power of genomic medicine, but also the importance of achieving a genetic diagnosis as quickly as possible.
Accelerating genomic analysis in epilepsy
Congenica Neuro has been specially configured to provide accurate and intuitive rapid response analysis of neurodevelopmental disorders (NDD) using an expertly curated gene panel.
Due to the importance of de novo variants in NDDs and epilepsy, Congenica Neuro has been configured to highlight de novo variants contained within genes. This provides you with the greatest chance of finding pathogenic variants in patients.
Furthermore, due to the increasing number of gene-specific therapeutic interventions, Congenica has curated a list of genes where there is published evidence for effective treatment. If the causative gene is contained within this list, Congenica can identify potential treatment options that could be considered during a clinical assessment.
We thank Dr Alasdair Parker, Consultant Paediatric Neurologist, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK and Berge A. Minassian, M.D., Professor in the Departments of Pediatrics, Neurology and Neurotherapeutics, and Neuroscience at UT Southwestern, USA, for their contribution to this article.